Characterization of human killer cell reactivity against porcine target cells: differential modulation by cytokines

The cytotoxic cell response to porcine cells by human lymphocytes, and the modulation of cytolytic cellular activity by human cytokines were investigated. Human peripheral blood mononuclear cells (PBMC) and purified lymphocyte subsets were co-cultured with fresh irradiated porcine stimulator cells and examined for the development of lytic activity and for their proliferative response. Porcine target cells included a new cell line, MS-PBMC-J2 (designated J2; SLA-DR+MHC class I+CD2+CD3 CD8+CDI6+CD45+), aortic and microvascular endothelial cells. Initial results showed that natural killer (NK) cells were fivefold more efficient in killing porcine target cells compared with T cells. IL-12 augmented the killing of porcine target cells by human NK cells beyond that induced by stimulation with cells alone. In contrast, IL-2 and IL-15 often induced substantial human NK cell mediated killing of porcine target cells, including endothelial cells in the case of IL-2 where such targets were examined, even in the absence of stimulator cells. Finally, neither IL-18 nor IL-8 had any effect beyond background on NK cell mediated killing of porcine target cells. These findings show that cytokines that would be produced in a xenograft setting clearly modulate the ability of human cytolytic cells to kill porcine targets. In addition, fresh unstimulated human NK cells lysed J2 and porcine aortic endothelial cells, but not porcine microvascular endothelial cells, suggesting the possibility of rapid attack of xenografts by NK cells, and differential susceptibility of endothelial cells from different vascular structures to this attack.